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Open AccessArticle

Chromate Oxidation of α-Nitro Alcohols to α-Nitro Ketones: Significant Improvements to a Classic Method

Department of Chemistry, Idaho State University, Campus Box 8023, Pocatello Idaho, 83209 USA
*
Author to whom correspondence should be addressed.
Molecules 2005, 10(12), 1458-1461; https://doi.org/10.3390/10121458
Received: 12 September 2005 / Accepted: 8 October 2005 / Published: 31 December 2005

Abstract

A series of eight alkyl and aryl α-nitro ketones were prepared by the potassium dichromate oxidation of the corresponding nitro alcohols. Short reaction times allowed for the easy isolation of pure nitro ketones that are devoid of starting materials and/or other oxidation side products.
Keywords: Nitroalcohols; nitroketones; chromate oxidation. Nitroalcohols; nitroketones; chromate oxidation.

Introduction

Our interest in α-nitro ketones stems from their usefulness in the synthesis of alkyl substituted pyrazines [1]. A literature search revealed a limited number of procedures for their preparation. α-Nitro ketones have been prepared in a one pot procedure by a solvent free nitroaldol (Henry reaction) reaction followed by oxidation to the corresponding ketone using wet-alumina supported chromium(VI) oxide [2], by the base catalyzed nitroaldol reaction using alumina supported potassium fluoride, followed by oxidation using CrO3 along with the addition of montmorillonite K 10 [3], or by the sodium dichromate oxidation of α-nitro alcohols [4] formed from the Henry reaction [5]. Other general methods for the oxidation of primary and secondary alcohols have been reported and these include the use of PCC [6] and the Swern [7] oxidation reactions. Finally α-nitro ketones can be prepared through the reaction of acyl imidazoles with nitroalkanes in the presence of lithium hydride in dimethyl sulfoxide [8].

Results and Discussion

This series of compounds reported here was prepared by a modified version of the sodium dichromate oxidation [4]. In the method used by Hurd and Nilson [4] the sulfuric acid solution was added to a mixture of the alcohols and sodium dichromate over a period of six hours, followed by long mixing periods (2–72 hours), depending on the nitro ketone prepared. In our modification of the procedure (given below), the nitro alcohol was gradually added to the potassium dichromate solution followed by a ten-minute stirring period, then the drop-wise addition of the sulfuric acid solution over a period of one hour. After the sulfuric acid addition is complete, the reaction is terminated by the addition of water, followed by extraction and purification.
This method led to yields between 85-95%, with minimal purification, as compared to literature yields of 68-86% [2], 76-90% [3] and 39-74% [4], which required more time and, in some cases, complex methods. It should be noted that NMR spectral analysis of the crude material (prior to Kugelrohr distillation) showed the compounds to be very pure, and thus they can be used directly in most applications.
Molecules 10 01458 i001
Entry #R1R2Yield % of 2*
2aCH3CH395
2bC2H5CH395
2cCH3(CH2)2CH393
2dCH3(CH2)3CH393
2eCH3(CH2)5CH387
2fCH3(CH2)6CH385
2gCH3CH2CH(CH3)290
2hCH3C6H595
* Yield of 100% pure isolated product; # Nitro alcohols a-g were prepared using the Henry reaction [9].

Conclusions

We have presented a facile route for the formation of α-nitroketones, useful intermediates in heterocyclic synthesis.

Experimental

General

All 1H- and 13C-NMR spectra were recorded in CDCl3 on a Varian Mercury NMR spectrometer operating at 300 and 100 MHz, respectively. Chemical shifts are expressed in ppm relative to TMS as an internal standard. J values are given in hertz. Final products were purified by Kugelrohr distillation using a Büchi B-580 Glass Oven. Starting materials were purchased from Aldrich and used without further purification.

General Procedure for the Oxidation Reaction.

Potassium dichromate (0.069 mol) and water (35 mL) were mixed with constant mechanical stirring in a 3-necked flask fitted with a condenser and an addition funnel. The corresponding nitro alcohol 1a-h (0.13 mol) was gradually added to the cooled stirring solution and stirring was continued for another 10 minutes. A cooled solution of H2SO4 (30 mL) and water (18 mL) was then added drop-wise over a period of 1 hr., after which water (100 mL) was introduced into the reaction mixture. The mixture was extracted with dichloromethane (3 x 150 mL), followed by subsequent washing with water (200 mL) and 5% sodium carbonate (200 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and the solvent evaporated in vacuo. The liquid obtained was distilled using a Kugelrohr apparatus to give the desired nitroketones 2a-2h.
3-Nitro-2-butanone (2a) [4]: 1H-NMR δΗ: 1.7 (d, 3H, CH3); 2.25 (s, 3H, CH3); 5.2-5.3 (q, 1H, CH).
3-Nitro-2-pentanone (2b) [4]: 1H-NMR δΗ: 1.05 (t, 3H, CH3); 2.0-2.2 (m, 2H, CH2, diastereotopic protons); 2.3 (s, 3H, CH3); 5.1 (dd, 1H, CH; J=6, J=10); 13C-NMR δC: 193.5 (CO); 93.0 (CH), 26.5, 10.0 (2 CH3); 22.5 (CH2); COSY [10].
2-Nitro-3-hexanone (2c): 1H-NMR δΗ: 0.95 (t, 3H, CH3); 1.61 (m, 2H, CH2); 1.75 (d, 3H, CH3); 2.6 (t, 2H, CH2); 5.25 (q, 1H, CH); 13C-NMR δC: 200.0 (CO); 89.5 (CH); 41.0, 17.0 (CH2), 13.0 (CH3).
2-Nitro-3-heptanone (2d): 1H-NMR δΗ: 0.95 (t, 3H, CH3); 1.35(m, 2H, CH2); 1.6 (m, 2H, CH2); 1.75 (d, 3H, CH3); 2.6 (t, 2H, CH2); 5.25 (q, 1H, CH); 13C-NMR δC: 200.0 (CO); 89.5 (CH), 39.5, 26.0, 22.0 (CH2); 16.0, 14.0 (CH3).
2-Nitro-3-nonanone (2e): 1H NMR δΗ: 0.9 (t, 3H, CH3); 1.3 (m, 6H, 3CH2); 1.65 (m, 2H, CH2); 1.7 (d, 3H, CH3); 2.55 (t, 2H, CH2); 5.25 (q, 1H, CH); 13C-NMR δC: 200.0 (CO); 89.5 (CH); 39.5, 31.0, 29.5, 22.0(CH2); 15.0, 14.0 (CH3).
2-Nitro-3-decanone (2f): 1H-NMR δΗ: 0.8 (t, 3H, CH3); 1.3 (m, 6H, 3CH2); 1.52 (m, 2H, CH2); 1.65 (m, 2H, CH2); 1.7 (d, 3H, CH3); 2.6 (t, 2H, CH2); 5.25 (q, 1H, CH); 13C-NMR δC: 200.0 (CO); 89.5 (CH); 39.7, 31.9, 29.1, 29.0, 23.6, 22.8 (CH2); 15.2, 114.2 (2CH3).
5-Methyl-2-nitro-3-hexanone (2g): 1H-NMR δΗ: 0.8 (d, 6H, 2CH3), 1.55 (d, 3H, CH3), 2.06 (m, 1H, CH), 2.41 (d, 2H, CH2), 5.05 (q, 1H, CH-NO2); 13C-NMR δC: 202.0 (CO), 95.3 (CH), 47.5 (CH2), 22.9 (CH), 22.0, 10.1(CH3).
2-Nitro-1-phenylpropanone (2h) [8]: 1H-NMR δΗ: 1.8 (d, 3H, CH3); 6.2 (q, 1H, CH); 7.4-8.0 (m, 5H, arom-H); 13C-NMR δC: 190.0 (CO); 136.0, 134.0, 129.0, 128.0 (arom); 84.5 (CH), 16.5 (CH3).

Acknowledgements

The authors thank the National Science Foundation for providing the funds for the purchase of the Varian Mercury 300 NMR (Award # 9980793) and the Fulbright Commission of Egypt to providing living expenses for TAE.

References and Notes

  1. Sato, N; Matsura, T. J. Chem. Soc. Perkin Trans. 1. 1996, 2345.
  2. Ballini, R; Bosica, G; Parrini, M. Tetrahedron Lett. 1998, 39, 7963.
  3. Mélot, J-M; Françoise, T-B; Foucaud, A. Tetrahedron Lett. 1986, 27, 493.
  4. Hurd, C. D; Nilson, M. E. J. Org. Chem. 1955, 20, 927.
  5. Seebach, D; Beck, A. K; Mukhopadhyay, T; Thomas, E. Helv. Chim. Acta 1982, 65, 1101.
  6. Corey, E. J; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647.
  7. Omura, K; Swern, D. Tetrahedron 1978, 34, 1651.Mancuso, A. J; Swern, D. Synthesis 1981, 3, 165.
  8. Crumbie, R. L; Nimitz, J. S; Mosher, H. S. J. Org. Chem. 1982, 47, 4040.
  9. Henry; Battice, De. Bull. Acad. Roy. Belg. 1898, 36, 149, [Chem. Zentr. 1898, II, 887].Henry. Ber. 1899, 32, 865.
  10. The 1H-NMR spectrum of 2b is interesting in that the resonance at 5.1 ppm appears as a doublet of doublets. The connectivity of the –CH(NO2)CH2CH3 was verified by a COSY experiment: the dd at δ 5.1 correlates with the m at δ 2.1, which correlates with the t at δ 1.05. A simple rigid search of the rotation barrier about the C2-C3 bond using CAChe molecular modeling software gave a rotational barrier of 82 kcal/mole. This indicates that the barrier to rotation is large and explains the observed dd at 5.1 ppm for 2b.
  • Sample Availability: Available from the authors.
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